Vitamin A and its derivatives (retinoids) affect processes as diverse as growth, vision, morphogenesis and reproduction. Clinically, retinoids are useful in the treatment of many skin diseases including ichthyosis, psoriasis, and acne vulgaris. They are also used in the management of dermal lymphoma and other cancers. Undesired side effects range from general toxicity to malformations in fetuses born from mothers who have taken retinoids for acne treatment. In spite of intensive research, the molecular mechanisms which govern retinoid action have remained unclear. A crucial advance toward understanding retinoid action has been accomplished through isolation of specific nuclear receptors for retinoic acid. The receptor isolated by us (RAR epsilon) is expressed in many epithelial tissues and can be expected to be a major mediator of retinoic acid in differentiation and proliferation processes. RAR epsilon has also been implicated in hepatocellular carcinoma development. Our research plan addresses the mechanism of retinoid action and the participation of RAR epsilon in differentiation and disease. We will study RAR epsilon expression in human tumor and normal tissue to investigate how frequently changes in RAR epsilon occur in neoplasms. The consequences of erroneous RAR epsilon tissue expression will be investigated in transgenic mice in which we direct RAR epsilon expression to specific tissues. This will allow us to test the hypothesis that expression of this receptor in liver can contribute to hepatoma development and will also provide information on RAR epsilon participation in morphogenesis. Hybrid receptors in which the ligand-binding domain has been exchanged with an estrogen-binding domain will be used to develop in vitro models to analyze the roles of RAR epsilon in cellular differentiation programs. We will also continue our receptor screening to isolate other retinoid receptors and possible RAR epsilon isoforms. Our planned analysis of the RAR epsilon promoter will yield important information on the regulation of RAR epsilon expression and may point to specific ways of interfering with this mechanism. Our studies will yield insight into how errors in this system may result in disease and oncogenesis. Our research results will be relevant to the clinical use of retinoids and should be helpful for the development of new retinoids and therapies where harmful side effects are eliminated or minimized.